Pediatric Diabetes Insipidus 

Diabetes is a Greek word meaning “siphon”; it is derived from the verb diabainein, which means “to stand with legs apart (as in urination) or to go through.” Insipidus is a Latin word meaning “without taste.” In contrast to diabetes mellitus, which involves the excretion of sweet urine, diabetes insipidus (DI) involves the passing of urine that is tasteless because of its relatively low sodium content.

DI is due either to (1) deficient secretion of arginine vasopressin (AVP)—also known as antidiuretic hormone (ADH)—by the pituitary gland (central or neurogenic DI) or to (2) renal tubular unresponsiveness to ADH (nephrogenic DI).

For central (neurogenic) DI, the treatment of choice is the synthetic ADH analogue desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]). Other useful medications include chlorpropamide and thiazide diuretics. Nephrogenic DI cannot be effectively treated with desmopressin, because the receptor sites are defective and the kidney is prevented from responding. Thiazide diuretics, amiloride, and indomethacin or aspirin are useful when coupled with a low-solute diet.

The basis of water loss in DI is distinct from that of water loss caused by diabetes mellitus. The renal tubular collecting ducts are unable to concentrate urine secondary to ADH deficiency or resistance.

The collecting duct concentrates urine by reabsorbing water, a function controlled by the posterior pituitary gland via secretion of AVP (ie, ADH). Reabsorption of sugars, amino acids, and virtually all electrolytes is completed by the time the urine has reached this segment of the nephron. Thus, the inability to conserve water by reabsorption in the collecting duct depletes body water but leaves sodium unaffected. The net result is an extremely diluted, increased urine output resulting in hypernatremia. Polydipsia follows, as the thirst mechanism urges replenishment of body water.

Secretion of ADH occurs in the posterior pituitary gland and is regulated at the paraventricular and supraoptic nuclei, which sense changes in osmolality. Destruction of the paraventricular or supraoptic nuclei or of the posterior pituitary by tumor, pressure, or surgical ablation results in decreased ADH secretion and central DI. Alternatively, DI may be idiopathic or inherited as either an autosomal dominant or an autosomal recessive trait (locus 20p13).

Nephrogenic DI arises from defective or absent receptor sites at the cortical collecting duct segment of the nephron (X-linked, vasopressin V2 receptor deficiency, locus Xq28) or defective or absent aquaporin, the protein that transports water at the collecting duct (autosomal recessive, locus 12q13).^{[1, 2, 3]} The X-linked variety of nephrogenic DI accounts for about 90% of all such cases.

As a consequence of one of these defects, the ducts do not appropriately respond to ADH. Normally, ADH is transported in the blood to receptor sites on the basolateral surface of the collecting duct membrane. Through a G protein–adenylate cyclase coupling, activation of the ADH receptor increases cyclic adenosine monophosphate (cAMP) production and stimulates protein kinase A, leading to increased recycling of the protein aquaporin in the plasma membrane.

In the presence of ADH stimulus, exocytic insertion of aquaporin into the apical, or luminal, surface of the tubule cell occurs. Aquaporin enhances water entry into the cell from the lumen. Absence of the ADH receptor does not allow this process to take place, causing inhibition of water uptake and polyuria. Alternatively, defective or absent aquaporin impairs the process in the presence of normal V2 receptors.

DI is due either to (1) deficient secretion of ADH by the pituitary gland (central or neurogenic DI) or to (2) renal tubular unresponsiveness to vasopressin (nephrogenic DI). Both genetic and nongenetic causes are known.^{[4, 5]}

Nongenetic causes

Nongenetic causes of DI include injuries. Typical injuries include head trauma, tumor, and neurosurgical procedures. At all ages, destructive lesions of the pituitary, the hypothalamus, or both are the most common cause of DI.

Genetic causes

Central DI with an autosomal dominant pattern inheritance is due to a mutation in the prepro-arginine vasopressin (prepro-AVP2) gene, mapped to locus 20p13. Central DI with diabetes mellitus, optic atrophy, and mental retardation (Wolfram syndrome) may be inherited in an autosomal recessive pattern (locus 4p16) or may be due to mitochondrial deletions.

X-linked nephrogenic DI occurs from mutations in the antidiuretic arginine vasopressin V2 receptor (AVPR2) gene, mapped to Xq28.^{[2, 6, 7]} Nephrogenic DI with an autosomal dominant or recessive pattern is due to mutations in the gene designated AQP2; this gene directs water channel formation in the distal membrane and has not yet been mapped.

United States statistics

Tumors, infiltrative lesions, malformations, and neurosurgical procedures are the most common causes of central DI. Of the genetic etiologies, the overall incidence in the general population is estimated to be 3 cases per 100,000 population (0.003%). The male-to-female ratio is 60:40. X-linked nephrogenic DI is very rare, although it exceeds the recessive variety in frequency by a ratio of 9:1. The rate of mutation for males is 4 cases per million population.

Age-related demographics

DI occurs across a wide age range. Children who present with autosomal recessive central DI are generally younger than 1 year; those who present with autosomal dominant central DI are often older than 1 year. Nephrogenic DI (including X-linked, autosomal dominant, and autosomal recessive forms) develops in early infancy, often in neonates younger than 1 week.

Sex-related demographics

Central DI secondary to hypothalamic-pituitary lesions occurs at random and should, therefore, be evenly distributed between the sexes. Autosomal dominant and autosomal recessive central DI occur equally in both sexes. Nephrogenic DI caused by an X-linked mutation affects only males. Autosomal dominant and autosomal recessive forms of nephrogenic DI equally affect both sexes.

Long-term survival in cases of central DI depends on the precipitating cause. In primary central DI, the prognosis is excellent with early recognition and appropriate desmopressin therapy.

The earlier onset of nephrogenic DI and the reduced ability to treat this variety of the disease renders the child more prone to attention deficit, hyperactivity, learning disorders, and psychomotor delay.

As long as water remains available at all times to replace the massive losses, long-term survival is not in question.

Parents must be educated regarding water replacement in infants and young children who cannot express thirst or access fluids without assistance. Gastrointestinal illnesses that cause decreased intake, increased stool losses, or both must receive early and serious attention to prevent life-threatening electrolyte and fluid balance abnormalities. (See the videos below.)